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The intestinal microbiome is emerging as a critical factor in health and disease. The microbes, although spatially restricted to the gut, are communicating and modulating the function of distant organs such as the brain. Stroke and other neurological disorders are associated with a disrupted microbiota. In turn, stroke-induced dysbiosis has a major impact on the disease outcome by modulating the immune response. In this review, we present current knowledge on the role of the gut microbiome in stroke, one of the most devastating brain disorders worldwide with very limited therapeutic options, and we discuss novel insights into the gut-immune-brain axis after an ischemic insult. Understanding the nature of the gut bacteria-brain crosstalk may lead to microbiome-based therapeutic approaches that can improve patient recovery.

OBJECTIVE To confirm that patients admitted to hospital with a head injury benefit from a routinely offered early intervention service. PATIENTS AND METHODS A mixed rural and urban Health District of 560 000 people with two accident and emergency departments provided the setting. Existing routine services for most patients with head injury are minimal. All patients aged 16–65 years admitted to hospital after a head injury of any severity, with or without other injuries entered the trial. Prospective randomisation, with a block randomisation procedure was used to allocate all eligible patients to either: a group offered an additional service by a specialist team; or a group receiving existing standard services. Patients were assessed at follow up six months after injury. The primary outcome measure was the Rivermead head injury follow up questionnaire, a validated and reliable measure of social disability. The Rivermead post-concussion symptoms questionnaire was used to estimate severity of post-concussion symptoms. Each patient in the trial group was contacted 7–10 days after injury, and offered assessment and interventions as needed. These initially focused on the provision of information, support, and advice. Forty six per cent of patients in the trial group also received further outpatient intervention or additional support by telephone. RESULTS 314 patients were registered: 184 were randomised into the trial group, 130 into the control group. For prognostic data, the groups were comparable at randomisation, and remained comparable when assessed at six months. 132 trial and 86 control patients were followed up at six months after injury. Patients’ post-traumatic amnesia ranged from mild (n=79, 40%), and moderate (n=62, 32%), to severe (n=38, 19%) and very severe (n=17, 9%). The trial group patients had significantly less social disability (p=0.01) and significantly less severe post-concussion symptoms (p=0.02) at follow up at six months after injury than the control group patients. CONCLUSIONS The early interventions offered by a specialist service significantly reduced social morbidity and severity of post-concussion symptoms in trial group patients at six months after head injury. Recommendations about how specialist services should be targeted are made both in the light of these results and those from a previous randomised controlled trial.

Key Points An increased understanding of the molecular biology of metastatic processes, including cell migration, blood–brain barrier penetration, angiogenesis and tumour proliferation, is providing new opportunities for the development of targeted therapies Advances in MRI, incorporating spectroscopy and perfusion techniques, and tracers unique to metastases, provide additional information on responses to treatment and enable the earlier detection of new tumours Improvements in intraoperative tumour identification using MRI and fluorescent agents maximize the likelihood of complete tumour resection and minimize injury to normal tissue Reduction of radiation-induced cerebral injury and cognitive decline through repeated use of stereotactic radiosurgery or hippocampal-avoidance whole-brain radiotherapy provide useful options for individuals with advanced cerebral metastatic disease Targeted therapy is beneficial in molecularly-selected tumours, including erlotinib in EGFR -mutant lung tumours, crizotinib in lung carcinomas with EML4 – ALK translocations, trastuzumab in HER2 + breast cancer and dabrafenib in BRAF -mutant melanoma Brain metastasis is an important complication associated with a number of common primary cancers, including lung and breast cancers, and melanoma, and has major effects on patient morbidity and mortality. This Review discusses the advances in our understanding of the molecular biology of brain metastases, and how this knowledge has influenced the imaging, surgical, radiological and pharmaceutical approaches involved in the management of brain metastasis. Metastatic tumours involving the brain overshadow primary brain neoplasms in frequency and are an important complication in the overall management of many cancers. Importantly, advances are being made in understanding the molecular biology underlying the initial development and eventual proliferation of brain metastases. Surgery and radiation remain the cornerstones of the therapy for symptomatic lesions; however, image-based guidance is improving surgical technique to maximize the preservation of normal tissue, while more sophisticated approaches to radiation therapy are being used to minimize the long-standing concerns over the toxicity of whole-brain radiation protocols used in the past. Furthermore, the burgeoning knowledge of tumour biology has facilitated the entry of systemically administered therapies into the clinic. Responses to these targeted interventions have ranged from substantial toxicity with no control of disease to periods of useful tumour control with no decrement in performance status of the treated individual. This experience enables recognition of the limits of targeted therapy, but has also informed methods to optimize this approach. This Review focuses on the clinically relevant molecular biology of brain metastases, and summarizes the current applications of these data to imaging, surgery, radiation therapy, cytotoxic chemotherapy and targeted therapy.

Loss of cognitive function is one the most devastating manifestations of ageing and vascular disease. Cognitive decline is rapidly becoming an important cause of disability worldwide and contributes significantly to increased mortality. There is growing evidence that hypertension is the most important modifiable vascular risk factor for development and progression of both cognitive decline and dementia. High blood pressure contributes to cerebral small and large vessel disease resulting in brain damage and dementia. A decline in cerebrovascular reserve capacity and emerging degenerative vascular wall changes underlie complete and incomplete brain infarcts, haemorrhages and white matter hyperintensities. This review discusses the complexity of factors linking hypertension to brain functional and structural changes, and to cognitive decline and dementia. The evidence for possible clinical markers useful for prevention of decreased cognitive ability, as well as recent data on vascular mechanism in the pathogenesis of cognitive decline, and the role of antihypertensive therapies in long-term prevention of late-life cognitive decline will be reviewed.

Subarachnoid hemorrhage (SAH) is a catastrophic form of stroke responsible for significant morbidity and mortality. Oxidative stress, inflammation, and neuronal apoptosis are important in the pathogenesis of early brain injury (EBI) following SAH. Preconditioning exercise confers neuroprotective effects, mitigating EBI; however, the basis for such protection is unknown. We investigated the effects of preconditioning exercise on brain damage and sensorimotor function after SAH. Male rats were assigned to either a sham-operated (Sham) group, exercise (Ex) group, or no-exercise (No-Ex) group. After a 3-week exercise program, they underwent SAH by endovascular perforation. Consciousness level, neurological score, and sensorimotor function were studied. The expression of nuclear factor erythroid 2 p45-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), 4-hydroxynonenal (4HNE), nitrotyrosine (NT), ionized calcium-binding adaptor molecule 1 (Iba1), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 1β (IL-1β), 14–3-3γ, p -β-catenin Ser37, Bax, and caspase-3 were evaluated by immunohistochemistry or western blotting. The terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end labeling (TUNEL) assay was also performed. After SAH, the Ex group had significantly reduced neurological deficits, sensorimotor dysfunction, and consciousness disorder compared with the No-Ex group. Nrf2, HO-1, and 14–3-3γ were significantly higher in the Ex group, while 4HNE, NT, Iba1, TNF-α, IL-6, IL-1β, Bax, caspase-3, and TUNEL-positive cells were significantly lower. Our findings suggest that preconditioning exercise ameliorates EBI after SAH. The expression of 4HNE and NT was reduced by Nrf2/HO-1 pathway activation; additionally, both oxidative stress and inflammation were reduced. Furthermore, preconditioning exercise reduced apoptosis, likely via the 14–3-3γ/ p -β-catenin Ser37/Bax/caspase-3 pathway.

Emerging stroke literature suggests that treatment of experimentally induced stroke with stem cells offered post-stroke neuroprotection via exosomes produced by these cells. Treatment with exosomes has great potential to overcome the limitations associated with cell-based therapies. However, in our preliminary studies, we noticed that the exosomes released from human umbilical cord blood-derived mesenchymal stem cells (MSCs) under standard culture conditions did not improve the post-stroke neurological outcome. Because of this apparent discrepancy, we hypothesized that exosome characteristics vary with the conditions of their production. Specifically, we suggest that the exosomes produced from the cocultures of regular and oxygen–glucose-deprived (OGD) MSCs in vitro would represent the exosomes produced from MSCs that are exposed to ischemic brain cells in vivo, and offer similar therapeutic benefits that the cell treatment would provide. We tested the efficacy of therapy with exosomes secreted from human umbilical cord blood (HUCB)-derived MSCs under in vitro hypoxic conditions on post-stroke brain damage and neurological outcome in a rat model of transient focal cerebral ischemia. We performed the TTC staining procedure as well as the neurological tests including the modified neurological severity scores (mNSS), the modified adhesive removal (sticky-tape), and the beam walking tests before ischemia and at regular intervals until 7 days reperfusion. Treatment with exosomes obtained from the cocultures of normal and OGD-induced MSCs reduced the infarct size and ipsilateral hemisphere swelling, preserved the neurological function, and facilitated the recovery of stroke-induced rats. Based on the results, we conclude that the treatment with exosomes secreted from MSCs at appropriate experimental conditions attenuates the post-stroke brain damage and improves the neurological outcome.

The pro-inflammatory activity of interleukin 17, which is produced by the IL-23/IL-17 axis, has been associated with the pathogenesis of traumatic brain injury (TBI). The study investigated the potential role of IL-17 in secondary brain injury of TBI in a rat model. Our data showed that the levels of IL-17 increased from 6 h to 7 days and peaked at 3 days, in both the CNS and serum, which were consistent with the severity of secondary brain injury. The IL-23 inhibitor suberoylanilide hydroxamic acid (SAHA) treatment markedly decreased the expressions of IL-17 and apoptosis-associated proteins cleaved caspase-3 and increased the protein ratio of Bcl-2 (B cell lymphoma/leukemia-2)/Bax (Bcl-2-associated X protein). Meanwhile, neuronal apoptosis was reduced, and neural function was improved after SAHA treatment. This study suggests that IL-17 is involved in secondary brain injury after TBI. Administering an IL-23 inhibitor and thereby blocking the IL-23/IL-17 axis may be beneficial in the treatment of TBI.

Acute ischemic stroke is a leading cause of death and disability worldwide. Several recent clinical trials have shown that endovascular treatment improves clinical outcomes among patients with acute ischemic stroke. To provide an overall and precise estimate of the efficacy of endovascular treatment predominantly using second-generation mechanical thrombectomy devices (stent-retriever devices) compared to medical management on clinical and functional outcomes among patients with acute ischemic stroke. MEDLINE, EMBASE, Cochrane Collaboration Central Register of Controlled Clinical Trials, Web of Science, and NIH ClinicalTrials.gov were searched through November 2015. Searches returned 3,045 articles. After removal of duplicates, two authors independently screened titles and abstracts to assess eligibility of 2,495 potentially relevant publications. From these, 38 full-text publications were more closely assessed. Finally, 5 randomized controlled trials of endovascular treatment with predominant use of retrievable stents were selected. Three authors independently extracted information on participant and trial characteristics and clinical events using a standardized protocol. Random effects models were used to pool endovascular treatment effects across outcomes. The primary outcome was better functional outcome as measured on the modified Rankin Scale at 90 days of follow-up. Secondary outcomes included all-cause mortality and symptomatic intra-cerebral hemorrhage. Five trials representing 1,287 patients were included. Overall, patients randomized to endovascular therapy experienced 2.22 times greater odds of better functional outcome compared to those randomized to medical management (95% CI, 1.66 to 2.98; P < 0.0001). Endovascular therapy was not associated with mortality [OR (95% CI), 0.78 (0.54, 1.12); P = 0.1056] or symptomatic intracerebral hemorrhage [OR (95% CI), 1.19 (0.69, 2.05); P = 0.5348]. Meta-regression analysis suggested that shorter times from stroke onset to groin puncture and from stroke onset to reperfusion result in better functional outcomes in ischemic stroke patients (P = 0.0077 and P = 0.0089). There were no significant differences in the beneficial effects of endovascular treatment on functional outcomes across categories of gender, age, stroke severity, ischemic changes on computed tomography, or intravenous tissue plasminogen activator administration. This meta-analysis demonstrated superior functional outcomes in subjects receiving endovascular treatment compared to medical management. Further, this analysis showed that acute ischemic stroke patients may receive enhanced functional benefit from earlier endovascular treatment.

Oxidative stress is well known to play a pivotal role in cerebral ischemia–reperfusion injury. The nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway has been considered a potential target for neuroprotection in stroke. 11-Keto-β-boswellic acid (KBA) is a triterpenoid compound from extracts of Boswellia serrata . The aim of the present study was to determine whether KBA, a novel Nrf2 activator, can protect against cerebral ischemic injury. Middle cerebral artery occlusion (MCAO) was operated on male Sprague–Dawley rats. KBA (25 mg/kg) applied 1 h after reperfusion significantly reduced infarct volumes and apoptotic cells as well as increased neurologic scores at 48 h after reperfusion. Meanwhile, posttreatment with KBA significantly decreased malondialdehyde (MDA) levels, restored the superoxide dismutase (SOD) activity, and increased the protein Nrf2 and HO-1 expression in brain tissues. In primary cultured astrocytes, KBA increased the Nrf2 and HO-1 expression, which provided protection against oxygen and glucose deprivation (OGD)-induced oxidative insult. But knockdown of Nrf2 or HO-1 attenuated the protective effect of KBA. In conclusion, these findings provide evidence that the neuroprotection of KBA against oxidative stress-induced ischemic injury involves the Nrf2/HO-1 pathway.

Stroke remains a significant unmet clinical need with limited therapeutic options. The peculiar feature of ischemic stroke is the interruption in brain circulation, resulting in a cascade of detrimental cerebrovasculature alterations. Treatment strategies designed to maintain potency of the cerebrovasculature may protect against stroke. The present study assessed the effects of short bouts of exercise prior to stroke induction and characterized cerebral blood flow and motor functions in vivo. Adult Sprague–Dawley rats were exposed to a single short bout of exercise (30-min or 60-min forced running wheel) then subjected to transient middle cerebral artery occlusion (MCAO). Non-exercise stroke rats served as controls while non-stroke rats represented shams. Cerebral blood flow (CBF) was evaluated by laser Doppler at baseline (prior to MCAO), during MCAO, and during reperfusion. Behavioral tests using the elevated body swing test was conducted at baseline, day 0 (day of stroke), and at days 1 and 3 after stroke. Animals that received exercise displayed typical alterations in CBF after stroke, but exhibited improved motor performance compared to non-exercise rats. Exercised stroke rats showed a reduction in infarct size and an increased number of surviving cells in the peri-infarct area, with a trend towards prolonged duration of the exercise. Immunofluorescence staining and Western blot analysis of the peri-infarct area revealed increased levels of endothelial markers/angiogenesis markers, VEGF, VEGFR-2, and Ang-2, and endothelial progenitor cell marker CD34+ in exercise groups compared with the controls. These results demonstrated that prophylactic exercise affords neuroprotection possibly by improving cerebrovascular potency.